5-nitrohexahydropyrimidines and process for preparation thereof



- process for the preparation-thereof.

Patented Dec; 2-5, 1945 5-.NITR(lHEX-AHYDROPYRIMIDINES- AND PROCESS FOR PREPARATION THEREOF Murray Senkus, Terre Haute, Ind.

No Drawing,- Application July 29; 1944, SerialNo. 541,281.:

12 Claims.

inventiomrelates toiaznew series oi? nitro .genecontaining-ccmpoundsl More particularly it relates {to-5 i-nitrohexahydropyrimidines :andtoa 'Ihe-.-.com-. pounds-of .myzinvention maybe represented by thesfollowingl :general structural formula:

iii-N N-R on," on,"

oz \NOQ inwhichft. may be alkyl, aryl, hydroxymethyl or hydrogen and R represents-either 'alkyl; aralkyl,

aryl, 2hydroxyalkyl; 'dialkylaminoalkyl, furfuryl,

' Accordingg -to my invention, these 5 nitrohexa- I hydropyrimidines may be readily prepared by first adding fonnaldehyde to a cooled-solution of therequired amine to "produce the corresponding 'N=hy droxymethylamine, the formaldehyde being preferablyadded ina' ratio of three moles of formaldehyde to two of amine. This reaction is generally quite'exothernfic'in nature and it is usually desirable to cool the'reaction vessel with ice or other suitable'means, particularly if volatile low'molecular weight amines are employed. When the reaction has subsided; a suitable nitrohydrocarbon having-the nitro group attached to a primary carbonatom' is added in a molar concentration equivalent, to approximately one-half of that of the amine. After all of the nitrohydrocarbon'has been introduced, the reaction mixture is generally heated to about 70 C. in order to drive the reaction to completion. Upon completionof the reaction, the -5-.nitrohexahydropyrimidines which separate from the reaction. mixture as solids can be readily-purified by recrystallization from a suitable solvent such as petroleum dines maybe separated from the water layer. and

water-soluble impurities, shakenv again with water; separated, and dried over- .a suitable drying agent such-as anhydrous-sodium. sulfate. or an.- hydrous'calcium sulfates A modified and frequently preferred procedure for preparing 2 the 5enitrohexahydropyrimidines of my 'inventionrinvolves mixinga nitro. glycol witha: suitable primary amine, the two materials being preferably brought together in .a ratio of twomoles of amineto one of nitroglycolr Under these conditions, the nitroglycol dissociates into the :parent nitrohydrocarbon and formaldehyde, thusresultingjn the formation of a .reactionmixture containing an amine. anitrohydrocarbon, and. formaldehyde. In the. case of aromatic amines a small quantityof catalyst,such as 50% aqueous sodium hydroxide, should be employed. Thereafteniormaldehyde in the .form an aqueous solution, ortrioxymethylene, .is added to the mixture inan amount corresponding approximately to themolecular quantity of nitro glycol present. Upon completion ofthexeactionthe product is purified in. accordance with the methods outlined above.

Since bothof theabove described. procedures result in-the formation. of identical products, and since bothfundamentally involve reaction mixtures containingformaldehyde, a primary amine, andanitrohydrocarbon having the nitro group attached to a primary.carbon.atom,. it may be seen that the reactions occurring therein are mall/essential respects equivalent. It is therefore to be specifically understood that the terminology employed in certain of the appended process .claims is tobe construed to cover both of the ioregoingmodifications.

While I have indicated above that it is desirable to use .at least three moles of formaldehyde for eachmole of nitrohydrocarbon in the preparation. of the compounds of .my invention, it is possible to effect the desired reaction byemploying. lower proportions of formaldehyde; such as for example two moles for each mole of nitrohydrocarbom Theyields of S-nitrohexahydropyrimidine obtained, however; under such conditions are lower.

Reactiontemperatures may be employed ranging from'about 25--30 C; to reflux temperature .of

- room: temperature in the -.presence or cformaldehyde iii the reactants are permitted .to remain in contact with one another for a sufllcient period of 7 time..-.

Thereactionugenerallycan be eflected in the absence ulna -solvent. However, I have found it preferable in most instances to employ a suitable solvent such as benzene or a lower aliphatic alcohol, for example, methanol.

Any primary amine, aliphatic or aromatic, can be employed in my process and the structure of any particular amine utilized may vary widely. For instance, in addition to the utilization of any of the common aliphatic or aromatic amines such as methylamine,ethylamine, butylamine, aniline, naphthylamine, and the like, I may also employ with equal success certain aromatic diamines, such as N-(2-aminoisobutyl)-N-methyl-o-chloroaniline, N-(Z-aminoisobutyl) '-N-methylaniline,

N- (2-aminoisobutyl) -N-methyl-m-toluidine, N- (2-aminoisobutyl) -N-ethyl-p-aminobenzoic acid, and N-( 2 aminoisobutyl) N methylsulfanilic acid, and aliphatic diamines, such as N-(2- aminoisobutyl)dimethylamine, N-(2 aminoisobutyl) isopropylmethylamine, N- (2-aminoisobutyl) -bis-(1-methylhexyl) amine, N (2-aminoisobutyl-dioctadecyl) amine, -N-(2 aminoisobutyl) benzylmethylamine, N- (2 aminoisobutyl) -N- (1- phenylethyDmethylamine, N (2 aminoisobutyl)cyclohexylmethylamine, N-(2 aminoisobutyl) -N (1 methylcyclohexyl)methylamine, 5- amino-3-benzyl-2,2,5-trimethyl-3-aza-1-hexanol, N-(2-aminoisobutyl) bis (tetrahydrofurfuryl) amine, N-(2 aminoisobutyl) difurfurylamine, N- (Z-aminoisobutyl) piperidine, N (2-aminoisobutyl) -2,5-dimethylpyrr0lidine, N (Z-aminolsobutyl) morpholine, and the like.

The group of amines which I have designated as aromatic diamines may be conveniently prepared by catalytic reduction of the corresponding nitro amines under pressure, as described in copending application, U. S. Serial No. 459,447, filed September 23, 1942 by Harold G. Johnson. The nitro amines employed as starting materials for the synthesis of the aforesaid aromatic diamines may be prepared in accordance with the procedure described in copending application, U. S. Serial No. 473,523, filed January 25, 1943, by

' Harold G. Johnson. According to this procedure,

asecondary aromatic amine is reacted with a suitable monoor dihydric primary nitro alcohol in the presence of a basic catalyst, such as for example, sodium hydroxide, tributylamine, triethylamine, or benzylammonium hydroxide at a temperature of approximately 50 C.

The amines designated above as aliphatic diamines can readily be synthesized by catalytically reducing the corresponding nitro amines under pressure in accordance with the procedure described and claimed in my copending application, U. S. Serial No. 455,932, filed August 24, 1942. The nitro amines utilized as starting materials may be synthesized in accordance with the procedure described in my copending application, U. S. Serial No. 455,931, filed August 24, 1942. By this procedure, a secondary aliphatic amine is reacted with formaldehyde to form the corresponding N- hydroxymethyl monoor dialkyl amine, which is in turn reacted with an equimolecular quantity of a secondary nitroparaflin to produce the desired nitro amine. The preparation of such nitro amines is preferably carried out at temperatures of from between about 25-30 C. Temperatures above this range may be utilized but in doing so care should be exercised to avoid temperatures which cause the formaldehyde to be volatilized from the reaction mixture.

As examples of suitable nitrohydrocarbons which may be employed in my process, there may be mentioned m'tromethane, nitroethane, i-nitropropane, i-nitrobutane, phenylnitromethane. and

the like.

The process of my invention may be more specifically illustrated by the representive examples which follow:

Example I vessel which contained the mixture was immersed in water in order to lower the temperature of the mixture to about 70 and thus avoid a possible loss of nitroethane. The product began to crystallize in aboutthirty minutes. The mixture was allowed to stand at room temperature for about twenty hours. The product was isolated by flitering the mixture on a Buchner funnel and then it was dried in the air for twenty hours. The dried white crystalline product weighed 630 g.

It was purified by recrystallization from water;-

M. P. 151.8 C.

Analysis: Calculated for CnHzrNaOs:

H, 7.85. Found: C, 52.02; H, 7.66

Example II A mixture consisting of 20 g. of 2-nitro-2 phenyl-l,3-propanediol, 6 g. of methylamine in the form of a 31% aqueous solution (20 ml), and 7.5 ml. of 36% aqueous formaldehyde (3 g.) was heated to a temperature of about on a steam bath for one hour. Thereafter 500 ml. of benzene was added and the mixture evaporated until it became homogeneous. To the homogeneous mixture was then added with agitation 3 g. of charcoal, after which the latter was removed by filtration, The filtrate was next placed on the steam bath to evaporate off the benzene. The residue thus obtained consisted chiefly of crude 5-nitro- 5-phenyl-1,3-dimethylhexahydropyrimidine, To this residue was next added 400 ml. of petroleum ether and the mixture heated to boiling, after which it was allowed to stand overnight at room temperature. On filtration, 17 g. of yellow, waxy crystals were obtained. These were then recrystallized twice from petroleum ether yielding 11 g. of white crystalline 5-nitro-5-phenyl-1,3-dimethylhexahydropyrimidine melting at 97.4 C.

Analysis: Calculated forCuHnNaOz: C, 61.28;

H, 7.23. Found: C, 61.24; 1 1, 7.24.

Example III 'dropyrimidine.

Analysis? Calculated fOI'CzfiI-IsdNsDfi: N,-"14.49.

Found: N, 1436 11 9, 1373911120 0.9 386.=

The following data were determined forcer;

tain 5 nitrohexahydropyrimidines of my inven- 'a b nE aflQSi e iii e*fii ub a d in primary carbon atomi the formaldehydi being added in a ratio-chat least three moles to one of nitrohydrooarbon and twomoles -of primai-y 5 amine. tion prepared in accordance with the various pro- 4, A process f th r arat1 ni-=5. it bcedures outlined above. hexahydropyrimidines which comprises mixing TABLE Carbon Hydrogen Nitrogen Amine Nitroparaflin -nitrohexahydropyrimidine M c? "D" Cale. Found Cale. Found Cale. Found Benzylamine Nitroethane--- 5-nitro-l,3-d.ibenzyl-5-methyl- 113.5 70.15 69.05 7.

. hexahydropyrimidine. Do l-nitropropane. do 93.7 71.09 70.33 7.37 7.02 12.39 12.41 Methylamine Nitromethane. 5-nitro-1,3-dimethyI-5-hydroxy- 121 44.44 44.57 7.94 7.91

g ethylhexahydropyrimime. Do Nitroethane 5-nitro-1,3,5trimethylhexahydropyrimidine. Dol-nitropropane. 5 nitro-l,3-dimetl1y1- ethyl hexahydropyrimidine. Phenylnitro- 5-ni'tro-l,3-dimethyl-5-phenyl- 97.4 61.28 61.18 7.23 7.16 methane. hexahydropyrimidine. Isopr'opylanune.....v Nitromethane- 5-nitro-1,3-diisopropylhexa- 77 55.82 56.34 9.82 9.65

hydropyrimidine. D0-.--- ....do--.. 5-nitro-1,3-diisopropyl-5-hy- 137 53.88 54.29 9.38 9.10

droxymethylhexahydropyrimidine. D0 Nitroethane--. 5-nitro-1,3-diisopropy1-5- 40.9 57.64 58.09 -04 9. 9

g ethylhexahydropyrimime. l-methylheptyla- .do 5-nitro-1,3-bis (l-methyl- 140.5 16.05 16-47 mine. heptyl)5-methylhexahydropyrimidine. -dimethylammo-2, do 5-nitro-1,3-bis(ii-dimethyl- 0.9511 1,4720 17-90 2-d1rnethylproamino-2,2-dimethylpropyl)- pylamine. g methylhexahydropyrimime. -dibutyla1ninopro- .....do 5-nitro-1,3-bis(3-dlbutyla- 0.9386 1,4739 14-49 14.30

pylamine. minopropyl)-5-methylhexahydropyrimidine. Z-aminO-Z-mcthyl- ..d0 5-nitro-l,3-bis(1,1-dimethyl-2- 124 53.98 53.68 9.41 9.06

l-propenol. hydroxyethy1)- 5- methylhexahydropyrimidine. fi-amino-5-methyl-1, .-...d0 5-nitro-l,3-bis(1-methy1-3,5- 151.8 52.17 52.02 7.83 7.66

3-d1oxane. dioxaoyclohexyl)-5-methylhexahydropyrimidine. D0 l-nitropro- 5-nitro-1,3-bis(1-methyl-3, 105.6 53.48 51.76 8.36 7.95

pane. 5-dioxacyclohexyl)-5-ethylhexahydropyrlmidine. Aniline Nitroethane 5-nitro-i,3-diphenyl-5-methyl- 68.2 68.62 68.57 6.39 6-28 hexahydropyrimidine. Furfurylamineuuu ..do 5-nitro-1,3-dituriuryl-5-methyl- 179.1 15.7 16-4 hexahydropyrimidine.

1 N.P. of dihydrochloride. 2 CI content of dihydrochloride.

The 5-nitrohexahydropyrimidines of the type iluustrated and discussed above are useful in the preparation of numerous valuable organic compounds. Additional uses of these materials will be apparent to those skilled in the art.

My invention now having been described, what I claim is:

1. A process for the preparation of 5-nitrohexahydropyrimidines, which comprises bringing a primary amine into reaction with a nitrohydrocarbon having a nitro group attached to a primary carbon atom, in the presence of formaldehyde, the latter being employed in a ratio of at least two moles to one of nitrohydrooarbon and two moles of primary amine.

2. A process for the preparation of 5-nitrohexahydropyrimidines, which comprises bringing a primary amine into reaction with a nitrohydrooarbon having a nitro group attached to a primary carbon atom, in the presence of formaldehyde, the latter being employed in a ratio of at least three moles to one of nitrohydrooarbon and two moles of primary amine.

3. A process for the preparation of 5-nitrohexahydropyrimidines, which comprises adding formaldehyde to a primary amine to produce the corresponding N-hydroxymethylamine, and thereafter adding-to the resulting mixture at nitrohy- 3 M.P. of picrate. N content of picrate.

a primary amine with a. 2-nitro-1,3-propanediol in a molecular ratio of approximately two moles of said amine to one of 2-nitro-1,3-propanediol in the presence of formaldehyde, the remainder of the formaldehyde required for the preparation of the desired 5-nitrohexahydropyrimidine being furnished by the decomposition of said 2-nitro- 1,3-propanediol into formaldehyde and a nitrohydrooarbon having the nitro group attached to a primary carbon atom.

5. A process for the preparation of 5-nitrohexahydropyrimidine, which comprises mixing a primary amine with a 2-nitro-1,3-propanediol in a molecular ratio. of approximately two moles of said amine to one of 2-nitro-1,3-propanediol in the presence of at least one mole of formaldehyde, the remainder of the formaldehyde required for the preparation of the desired S-nitrohexahydropyrimidine being furnished by the decomposition of said 2-nitro-1,3-propanediol into formaldehyde and a nitrohydrooarbon having the nitro group attached to a primary carbon atom.

- 6. The process of claim 3 in which the nitrohydrocarbon is l-nitropropane and the primary amine is benzylamine.

'7. The processof claim 4 in which the 2-nitro- 1,3-propanediol is 2-nitro-2-phenyl-1,3-propanediol and the primary amine is methylamine.

8. The prooess oi claimjin which the z-nitro- V 11. 5 -Nitro-5-phenyi- 1,3 -dimethyihexahydro- 1,3-propanediol is 2-nitro-2-methyi-L3-propanepyrimidine. diol and the primary amine is 3-dibutylamino- 12. 5 -Nitro- 1,3 diisopropylhexahydropyrimipropyiamine. dine.

9. As new compositions of matter, 5-nitrohexa- 5 MURRAY BENKUB. hvdropyrimidines.

1o; 5-Nitro-5-methy1-L3-bis-(3- dibutyiaminopropyl) hexahydropyrimidine. 

